PROJECT SUMMARY Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States. The disease is characterized by the proliferation and accumulation of abnormal CD5+/CD19+ B cells in the blood and lymphoid organs. CLL is considered incurable aside from bone marrow transplantation. Although current therapies have increased overall CLL long-term survival, relapse and disease resistance often occur. Currently, the cellular origin of CLL is unknown, making it difficult to identify the cause of relapse. Classically, mature subsets of B cells - such as marginal and memory B cells - are suspected to be the populations of origin. The disease paradigm has traditionally assumed that stem and progenitor cells are non-participatory in disease pathogenesis. However, recent published observations suggest that CLL may originate from populations of early hematopoietic stem cells (HSC). HSCs from CLL patients have been shown to form abnormal CD5+/CD19+ B cells when grown in mice. Single-cell gene analyses of these CLL HSCs show overexpression of a transcription factor - GATA2 - compared to HSCs from normal healthy controls. GATA2 is critical in the development and growth of HSCs but its role in CLL and lymphopoiesis has not been studied. In other solid and hematological malignancies, abnormal stem cells are responsible for therapy resistance and relapse. Current CLL medical therapy focuses on targeting the mature cancerous B cells. However, this strategy is not designed to target hematopoietic stem cells?a population that I propose may contribute to disease relapse and therapy resistance. In this proposal, I seek to better understand CLL pathogenesis by first determining the role of HSCs in CLL development and second by investigating GATA2's function in both normal and CLL patient-derived HSCs. I hypothesize that CLL patient-derived HSCs are leukemia-initiating cells and that leukemia initiation depends on GATA2 signaling. Successful completion of this project will define the role of CLL HSCs in CLL development and would direct new curative therapies in CLL. It will also allow me to develop unique technical, critical thinking, and effective communication skills crucial to my goals of becoming an independent investigator in the future.